Ketamine Therapy and Its Interaction with Daily Medications

Nearly all patients undergoing Ketamine therapy for mood disorders and chronic pain conditions are also taking daily medications to manage their condition.

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One significant factor influencing the variability in treatment efficacy or the way that Ketamine feels to one patient vs. another may be the other medications that patients are taking. Generally speaking, most medications are not an issue when undergoing Ketamine treatments, but some do interact with Ketamine by either blocking its actions or enhancing its actions. This article reviews some of these medications and their impact on Ketamine treatment efficacy. 

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Medications that compete with Ketamine in the brain:

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Certain medications prescribed for mood disorders impact the same neurological pathways as Ketamine, thereby affecting Ketamine’s efficacy.

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• Benzodiazepines (e.g., Xanax, Ativan, Klonopin), often prescribed for anxiety, sleep issues, and muscle spasms, may prolong the time it takes for patients to feel better when undergoing Ketamine treatment. When patients who are prescribed Benzodiazepines undergo Ketamine treatment it is generally advisable to be on the lowest possible dose, particularly on treatment days. New data suggests that patients can still have success with KAP if concurrently taking low doses of benzodiazepines but might need more total sessions in the initial series.

• Lamotrigine, used for seizures and bipolar disorder, acts to decrease glutamate release in the brain. We often advise patients to hold Lamotrigine on the day of a session as it can make getting to a therapeutic level of Ketamine experience needed to support KAP if not held. Sometimes patients taking Lamotrigine will need a slight increase in Ketamine dosing to establish a therapeutic Ketamine level, which is very easy to provide.

• Lithium, a mood stabilizer for bipolar disorder, can enhance the effects of Ketamine as both stimulate similar signaling pathways in the brain. Lithium may bolster the anti-depressant effects of Ketamine. 

• Stimulants (ADHD medications, Adderall, Ritalin, Vyvanse, Concerta ) should be held the day of Ketamine treatments. Both stimulants and Ketamine can raise heart rate and blood pressure slightly but can be more profound when used together so should be avoided when possible.

• Opiates, new data suggests that taking opiates on infusion day may play into Ketamine effectiveness. We will generally advise patients to hold or reduce pain medications prior to and shortly after infusions. Which is often not an issue given Ketamines effects on treating pain.

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Medications that interact with Ketamine in the Liver

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-CYP2B6 Enzyme-

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The CYP450 enzymes in the liver, particularly the CYP2B6 group, are crucial for metabolizing Ketamine to norketamine, its main metabolite. Some medications, also metabolized by CYP2B6, can influence Ketamine levels:

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• Dexamethasone, a common steroid, induces CYP2B6, accelerating ketamine breakdown and decreasing its available levels

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• Orphenadrine (Norflex), a muscle relaxant, inhibits CYP2B6 and thereby slows ketamine breakdown, increasing its presence in the body

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Genetic variations, such as having polymorphisms of the CYP2B6*6 allele, may slow ketamine clearance from the body, potentially increasing unwanted side effects.

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CYP3A4 Enzyme

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The CYP3A4 enzyme, another group within the CYP450 family, metabolizes approximately half of all drugs on the market. This enzyme's extensive involvement in drug metabolism leads to many potential interactions. 

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- Rifampin - decreases Ketamine levels

- St John’s Wort - decreases Ketamine levels

- Ketoconazole - increases Ketamine levels

- Cimetidine (Tagamet) -  may theoretically increase Ketamine levels

- Grapefruit Juice - increases oral Ketamine levels

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For oral forms of Ketamine, such as troches (lozenges), these interactions are particularly significant due to high rates of liver metabolism.

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Increasing Ketamine levels through medication interactions isn't necessarily beneficial, as it may also elevate the risk of side effects from both Ketamine and the interacting medication, and Ketamine has a specific dose range in which it is effective for the treatment of mood disorders. 

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Conclusion

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The medications discussed are just a sample of those identified in peer-reviewed research to potentially interact with Ketamine therapy. Many other medications may also impact Ketamine therapy based on clinical observations, but conclusive scientific evidence may still be pending.

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Patients are urged to always consult with their prescribing doctor before making changes to their medications, as abrupt alterations can be hazardous. This article aims to inform, not to replace medical advice. Ketamine is a part of a comprehensive treatment plan for mental health and/or chronic pain relief. For optimal outcomes, collaboration between the patient, doctor, therapist, and ketamine provider is essential.

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We will go over your medications in intake and advise if any medication may need to be held on the day of infusion. Ketamine is a medication that has very few interactions but it is critical to ensure prior to getting started to started with treatment.

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References

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Albott, C. S., Shiroma, P. R., et al. (2017). The Antidepressant Effect of Repeat Dose Intravenous Ketamine Is Delayed by Concurrent Benzodiazepine Use. The Journal of Clinical Psychiatry, 78(03).

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https://www.psychiatrist.com/jcp/depression/benzodiazepine-use-delays-the-antidepressant-effect-of-ketamine/

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Anand, A., Charney, D. S., et al. (2000). Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine. Arch Gen Psychiatry, 57(Mar).

https://pubmed.ncbi.nlm.nih.gov/10711913/

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Chiu, C. T., Scheuing, L., et al. (2015). The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induces by Acute Ketamine in a Mouse Model of Stress. International Journal of Neuropsychopharmacology, 18(6).

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438544/

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Yanagihara, Y., Kariya, S., et al. (2001). Involvement of CYP2B6 in N-Demethylation of Ketamine in Human Liver Microsomes. The American Society for Pharmacology and Experimental Therapeutics, 29(6).

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https://pubmed.ncbi.nlm.nih.gov/11353758/

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Li, Y., Jackson, K. A., et al. (2015). CYP2B6*6 Allele and Age Substantially Reduce Steady-State Ketamine Clearance in Chronic Pain Patients: Impact on Adverse Effects. British Journal of Clinical Pharmacology, 80(2), 276-284.

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https://pubmed.ncbi.nlm.nih.gov/25702819/

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Rao, L. K., Flaker, A. M. et al. (2016). Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance. Anesthesiology, 125(6).

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https://pubmed.ncbi.nlm.nih.gov/27763887/

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Busti, A. J. (2015). Common Medications Classified as Weak, Moderate, and Strong Inhibitors of CYP3A4. Retrieved from Ebmconsult.com.

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https://www.ebmconsult.com/articles/medications-inhibitors-cyp3a4-enzyme

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Amouzadeh, H. R., Sangiah, S., et al. (1989). Effects of Some Hepatic Microsomal Enzyme Inducers and Inhibitors of Xylazine-Ketamine Anesthesia. Veterinary and Human Toxicology, 31(6), 532-534.

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https://pubmed.ncbi.nlm.nih.gov/2617834/

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